Factor V Leiden, Hormone Replacement Therapy, and Risk
of Venous Thromboembolic Events in Women With
David M. Herrington, Eric Vittinghoff, Timothy D. Howard, David A. Major, John Owen,
David M. Reboussin, Donald Bowden, Vera Bittner, Joel A. Simon, Deborah Grady, Stephen B. Hulley
Abstract—Oral contraceptive use in women with factor V Leiden is associated with increased rates of venous
thromboembolic events (VTEs). However, the effects of hormone replacement therapy (HRT) in postmenopausal
women with factor V Leiden are not known. A nested case-control study was conducted among women with established
coronary disease enrolled in 2 randomized clinical trials of HRT, the Heart and Estrogen/Progestin Replacement Study
(HERS) and the Estrogen Replacement and Atherosclerosis (ERA) trial. The Leiden mutation was present in 8 (16.7%)
of 48 cases with VTE compared with only 7 (6.3%) of 112 controls (odds ratio [OR]Leiden3.3, 95% CI 1.1 to 9.8;
P?0.03). In women without the factor V Leiden mutation, risk associated with HRT use was significantly increased
(ORHRT3.7, 95% CI 1.4 to 9.4; P?0.01). On the other hand, in women with the factor V Leiden mutation, the estimated
risk associated with HRT was increased nearly 6-fold, although the CIs were wide and included unity (ORHRT5.7, 95%
CI 0.6 to 53.9; P?0.13). The OR for women with the Leiden mutation who were also assigned to HRT compared with
wild-type women assigned to placebo was 14.1 (95% CI 2.7 to 72.4, P?0.0015). In women with the factor V Leiden
mutation who were treated with HRT, the estimated absolute incidence of VTE was 15.4 of 1000 per year compared
with 2.0 of 1000 per year in women without the mutation who were taking a placebo (P?0.0015). On the basis of these
data, in women with coronary disease, the estimated number needed to screen for factor V Leiden to avoid an
HRT-associated VTE during 5 years of treatment is 376. If factor V Leiden genotyping becomes less expensive, it could
be cost effective to screen for the presence of the mutation before instituting HRT in women with coronary disease.
(Arterioscler Thromb Vasc Biol. 2002;22:1012-1017.)
Key Words: cardiology ? risk factors for stroke ? genetics ? thrombosis risk factors
factor V Leiden mutation, renders factor Va relatively resistant
to degradation by the natural anticoagulant, activated protein C
(APC).2,3The presence of this mutation or its functional conse-
quence, APC resistance, is associated with an increased risk of
venous thromboembolic events (VTEs).1,4–6Risk for VTE
appears to be even higher in women with APC resistance or the
factor V Leiden mutation who are also pregnant7–11or who use
oral contraceptives.7,12–15The effect of hormone replacement
therapy (HRT) on the risk of VTE in women with APC
resistance is not well established. One observational study found
a multiplicative relationship between the effects of HRT and
APC resistance on VTE risk,16whereas a small randomized
clinical trial of oral HRT in women with previously verified
VTE failed to confirm such a relationship.17Determining the
relative and absolute impact of HRT and factor V Leiden on
n 1994, Bertina et al1described a single point mutation in the
gene coding for factor V. This mutation, referred to as the
VTE risk is especially important for older women or for women
with coronary disease, whose baseline risk of VTE is consider-
ably higher than that of healthy premenopausal women.18,19
See page 879
women with coronary disease and its impact on the relationship
between HRT and VTE in this population, we conducted a nested
case-control study among participants of 2 multicenter randomized
clinical trials of HRT in women with established coronary disease,
the Heart and Estrogen/Progestin Replacement Study (HERS) and
the Estrogen Replacement and Atherosclerosis (ERA) trial.
The details of the HERS20and ERA21trial designs and primary
results22,23have been previously reported. Participants were post-
Received February 19, 2002; revision accepted April 2, 2002.
From the Department of Internal Medicine, Sections on Cardiology (D.M.H., D.A.M.), Medical Genetics (T.D.H.), and Hematology and Oncology
(J.O.), and the Departments of Public Health Sciences (D.M.R.) and Biochemistry (D.B.), Wake Forest University School of Medicine, Winston-Salem,
NC; the Department of Epidemiology and Biostatistics (E.V., J.A.S., D.G., S.B.H.), University of California, San Francisco; and the Department of
Medicine (V.B.), University of Alabama at Birmingham.
Reprint requests to David M. Herrington, MD, MHS, Department of Internal Medicine/Cardiology, Wake Forest University School of Medicine,
Medical Center Boulevard, Winston-Salem, NC 27157-1040. E-mail email@example.com
© 2002 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol. is available at http://www.atvbaha.org DOI: 10.1161/01.ATV.0000018301.91721.94
menopausal women aged ?80 years with documented coronary
artery disease. The participating clinical centers included 22 aca-
demic or community hospitals scattered throughout the continental
United States. The exclusion criteria for both trials included a history
of deep vein thrombosis (DVT) or pulmonary embolism (PE). In
HERS, participants were randomly assigned to receive oral conju-
gated equine estrogen (0.625 mg daily) plus medroxyprogesterone
acetate (2.5 mg daily) or placebo and were followed for an average
of 4.1 years. In ERA, women were randomized to receive oral
conjugated equine estrogen (0.625 mg daily), estrogen plus me-
droxyprogesterone acetate (2.5 mg daily), or placebo and were
followed for 3.25 years.
At 4- to 6-month follow-up visits, women were queried about blood
clots in the legs or lungs or any hospitalizations. A positive reply
prompted retrieval of all pertinent medical records to verify the
occurrence of a VTE. A diagnosis of DVT required confirmation by
venography, impedance plethysmography, or ultrasound. A diagno-
sis of PE required confirmation by a segmental or larger ventilation/
perfusion mismatch on a nuclear lung scan or an intraluminal filling
defect by pulmonary angiography. VTEs were classified as idio-
pathic if they occurred in women without a preexisting diagnosis of
cancer or the occurrence of an inpatient hospitalization or lower
extremity or hip fracture within 3 months before the VTE. Events
were adjudicated by individuals who were unaware of treatment
assignment or factor V genotype.
In HERS, 47 (1.7%) of the women had a VTE (32 DVTs and 15
PEs). At the final follow-up visit, cases and 2 age- and clinic-
matched controls were asked to provide an additional specimen of
whole blood for factor V genotyping. For women who could not
return for the final visit or who had died, consent was sought from
them or their next of kin to use a previously collected Pap smear for
extraction of DNA and genotyping. Consent was obtained, and factor
V genotype was ascertained in 40 of 47 cases and 80 matched
controls. Three of the remaining 7 cases declined participation, 3 did
not have blood or a Pap smear available for analysis, and 1 matched
control had a Pap smear that did not yield enough DNA for
genotyping. In ERA, 8 (2.6%) of the women had a VTE (6 DVTs and
2 PEs). DNA for genotyping was available for all 8 cases. In view of
the smaller number of VTE cases in ERA, 4 age- and clinic-matched
controls were selected per case. For both cohorts, the study design
and conduct were approved by the Wake Forest University Institu-
tional Review Board.
Genotyping for the presence of the Leiden mutation (G1691A) in
the factor V gene was performed on DNA extracted from anony-
mously labeled peripheral blood leukocytes or cells retrieved from
Pap smears (Pap smear slides yielded ?200 ng DNA per slide). The
genomic region containing the mutation site was amplified by
polymerase chain reaction, and the presence of the Leiden mutation
was inferred from the observed cleavage pattern with the restriction
Baseline and on-study characteristics of the cases and controls were
compared within each study and in the combined data; random
effects models24were used for continuous variables, and conditional
logistic regression25was used for binary variables, to take account of
the matched case-control design. The association between factor V
genotype and risk of VTE was examined by using conditional
logistic regression models, again to take account of the matching and
to adjust for treatment assignment. Odds ratios (ORs) generated by
these models, accompanied by 95% CIs and nominal 2-tailed
probability values, were used to approximate relative risks. In
exploratory analyses, results from the 2 study cohorts were similar;
therefore, the data from the 2 cohorts were combined. Similarly,
preliminary analysis within the ERA cohort found no significant
difference between the effects of unopposed estrogen and estrogen
plus medroxyprogesterone acetate; thus, data from these 2 active
treatment arms were combined. Additional models were also exam-
ined with adjustment for potential risk factors for VTE, including a
previous diagnosis of cancer (excluding nonmelanoma skin cancer)
or myocardial infarction (MI), inpatient hospitalization, or lower
extremity or hip fracture within 90 days of the VTE, or use of aspirin
or statins documented during the most recent clinic visit before the
VTE. In these models, as well as in the initial comparison with cases,
on-trial risk factors for controls were evaluated at the time in days
since the randomization of VTE onset for the matched case. Tests for
additive and multiplicative interaction were performed by using
previously described methods.26
Characteristics of the VTE cases and controls from each
clinical trial cohort are summarized in Table 1. In the pooled
data, prior MI, cancer (other than nonmelanoma skin cancer),
or hospitalization within 90 days were significantly associ-
ated with occurrence of VTE, and there was a nonsignificant
trend toward increased risk among women with elevated
triglycerides or a recent lower extremity or hip fracture and in
women who did not use aspirin. In multivariate analyses, only
hospitalization within 90 days and a history of MI remained
significantly associated with VTE.
The Leiden mutation was present in 8 (16.7%) of the 48
cases of VTE compared with only 7 (6.3%) of the 112
controls (Table 2). On the basis of these numbers, the
estimated prevalence of factor V Leiden in the entire study
population was 6.4%. After the age- and clinic-matched
case-control design was taken into account and adjustments
were made for treatment assignment, the risk of VTE was
?3-fold greater in women with factor V Leiden compared
with women without the mutation (ORLeiden3.3, 95% CI 1.1 to
9.8; P?0.03). Similarly, the ORLeidenfor a DVT was 3.2 (95%
CI 1.0 to 10.3, P?0.05), and for a PE, it was 3.5 (95% CI 0.2
to 69.6, P?0.41). After additional adjustment for recent
hospitalization and prior MI, the ORLeidenfor VTE increased to
6.8 (95% CI 1.1 to 42.8, P?0.05). The number of cases was
too small to support fully adjusted models with stable
estimates for DVT or PE separately. Factor V Leiden was
present in 5 (16%) of the 31 women with idiopathic VTE and
3 (18%) of the 17 women with nonidiopathic VTE.
HRT use was associated with a ?3-fold increase in the risk
of VTE (OR 3.4, 95% CI 1.4 to 8.1; P?0.06). Adjustment for
factor V Leiden status resulted in a slightly higher estimate of
risk (ORHRT3.9, 95% CI 1.6 to 9.6; P?0.004). After addi-
tional adjustment for recent hospitalization and prior MI, the
risk associated with HRT use remained significant (ORHRT
4.8, 95% CI 1.3 to 17.5; P?0.02). Among women without
factor V Leiden, the ORHRTwas 4.5 (95% CI 1.2 to 16.9,
P?0.02; Table 3). In contrast, among the fewer women with
factor V Leiden, the OR for HRT suggested a ?10-fold
increase in risk compared with placebo; however, the CIs
were wide and included unity (ORHRT10.2, 95% CI 0.3 to
344; P?0.20). Compared with women without factor V
Leiden taking placebo, women with factor V Leiden taking
HRT had a 14-fold greater risk of VTE (ORHRT14.1, 95% CI
2.7 to 72.4; P?0.002). Despite the suggestion of excess risk
of HRT in women with factor V Leiden, formal tests for
additive or multiplicative interaction were negative.
Overall, 1.56% of the combined study cohort (n?3072)
suffered a VTE. If it is assumed that the prevalence of
factor V Leiden in the sample of controls was representa-
Herrington et alEstrogen and VTE Risk in Women With CHD
tive of all noncases, 2.08% of women with factor V Leiden
had a VTE versus 1.49% of the women without factor V
Leiden. If the variable length of follow-up among women
in the 2 studies is taken into account, the overall incidence
of VTE was 7.1 per 1000 women per year. In women
without factor V Leiden who were assigned to placebo, the
incidence of VTE was 2.0 (95% CI 0.8 to 3.2) events per
1000 women per year (Table 4). Treatment with HRT
increased the estimated incidence to 5.8 events per 1000
women per year (95% CI 4.5 to 7.1). In factor V Leiden
women treated with HRT, the incidence was further
increased to 15.4 (95% CI 3.5 to 27.3) events per 1000
women per year. On the basis of these estimates, if women
with coronary disease were screened for factor V Leiden
TABLE 1. Characteristics of the Case-Control Samples from HERS and ERA
vs Controls P
Minority, N (%)
Hypertension, N (%)*
Diabetes mellitus, N (%)*
Current smokers, N (%)
Sedentary lifestyle, N (%)†
Previous MI, N (%)
Total cholesterol, mg/dL
LDL cholesterol, mg/dL
HDL cholesterol, mg/dL
On-trial VTE risk factors
Cancer, N (%)‡
Recent statin use, N (%)¶
Recent aspirin use, N (%)¶
Recent coumadin use, N (%)
Continuous variables presented as mean? standard error.
*Hypertension classification based on response to the question, “Have you ever been told by a physician that you have hypertension
or high blood pressure?”; diabetes classification based on response to the question, “Have you ever been told by a physician that
you have diabetes, sugar diabetes, or high blood sugar?”
†Based on self-report of walking “seldom” or “none” (ERA) or “much less” or “somewhat less active than other women your age”
‡Any diagnosis of cancer (except non-melanoma skin cancer) before VTE.
§Lower extremity or hip fracture ?90 days before time of VTE diagnosis in the index case (measured as days since randomization).
?Any inpatient hospitalization.
¶Documented at most recent clinic visit before time of VTE diagnosis in the index case (measured as days since randomization).
TABLE 2. Distribution of Factor V Leiden Genotype by Study and Case-Control Status
Cases (n?48)Controls (n?112)
HERSERA HERSERAOR†95% CIP
? ? ?? ? ?
0.05 1.0–10.3 N/A
? ? ?? ? ?
? ? ?? ? ?
*Based on conditional logistic regression taking into account age- and clinic-matched case-control design and adjusting for treatment assignment
(HRT versus placebo).
†Also adjusted for a history of previous MI and hospitalization.
‡Two women had a DVT and a PE.
1014Arterioscler Thromb Vasc Biol.
before initiating HRT and if HRT was withheld from
carriers of the mutation, the estimated number needed to
screen to prevent 1 VTE during 5 years of therapy would
These data reveal significant increases in the risk of VTE in
women with coronary disease who are carriers of the factor V
Leiden mutation. The 6.4% prevalence of the mutation in this
study population and the 3- to 6-fold relative increase in the
risk of VTE in women with the mutation are consistent with
earlier reports from studies of largely healthy normal sub-
jects.27,28However, because of the substantially higher base-
line risk of VTE in this group of women with coronary
disease, the absolute increase in risk associated with factor V
Leiden (?0.5% per year) was much higher than that in
healthier cohorts. Use of HRT in factor V Leiden–positive
women further increased the risk to ?1.5% per year. On the
basis of these data, in women with coronary disease, 1 DVT
might be prevented during a planned 5 years of treatment by
withholding HRT from the expected 24 Leiden-positive
women among 376 screened. For women who would use
HRT for 10 years, the number needed to screen would be 188.
The results of the present study are consistent with the
results of previous studies demonstrating a multiplicative
relationship between factor V Leiden or APC resistance and
exogenous estrogen use and the risk of VTE.12,16In a
case-control study of idiopathic VTEs, Lowe et al16observed
a 13-fold increased risk in HRT users with APC resistance
compared with women without APC resistance or HRT use;
this risk was very similar to the 15-fold excess risk observed
in the doubly exposed women in the present study.
The precise mechanism for the association between estro-
gen exposure and risk for VTE remains uncertain. Some,29–32
but not all, studies33indicate that oral contraceptive use or
pregnancy may result in an acquired form of APC resistance,
similar to the functional defect associated with the factor V
Leiden mutation. However, Douketis et al34failed to find
evidence of an effect of oral HRT on APC resistance.
Currently available data are also inconsistent regarding the
effects of HRT on thrombin generation or fibrinolytic
There are several limitations of the present study. The
number of cases is small, thereby limiting precision in the
estimates of the effects of factor V Leiden and the complexity
of the models that could be used to adjust for other covariates.
No information is available about concurrent thrombophilic
states in the study participants. Some evidence suggests that
factor V Leiden may be most important as a VTE risk factor
in the presence of other thrombophilic conditions. Protein C
deficiency,35protein S deficiency,36hyperhomocysteine-
mia,37and the prothrombin G20210A genotype38have all
been reported to further increase the risk of VTE associated
with factor V Leiden. The effects of HRT on the risk of VTE
in women with or without heart disease who also have such
thrombophilic conditions are not yet established. The esti-
mates of the risk of VTE in the clinical trial participants
reported in the present study may underestimate the risks in
the general population, because women with a prior history of
VTE or women with hypertriglyceridemia or advanced heart
failure were excluded from participation. In addition, after it
became clear that HRT was associated with an increased VTE
risk in HERS, the protocol was changed so that HRT was
withheld during acute hospitalizations, which may have
further minimized the overall risk in this study population.
Finally, the results of the present study may not apply to
women of other ethnic backgrounds. The prevalence of the
Leiden mutation is highest in northern Europeans and is
almost nonexistent in most Asian populations.27
It is also important to emphasize that the observations in
the present study are limited to women with established
coronary disease. The joint effects of HRT and factor V
Leiden in healthy women are not yet determined. In younger
women with factor V Leiden, oral contraceptives increase
risk by ?0.2 per 1000 women per year.39In the present study,
in women with coronary disease and factor V Leiden, the
increase in absolute risk associated with HRT use was
?40-fold greater (8.3 per 1000 women per year). It is difficult
TABLE 3. Effects of HRT on Risk for VTE by Factor V Leiden Genotype
(n?112) OR*95% CIP
OR† 95% CIP
? ? ?? ? ?
? ? ?? ? ?
? ? ?? ? ?
? ? ?? ? ?
0.20 0.6–53.9 0.3–344
*Based on conditional logistic regression taking into account age- and clinic-matched case-control design and adjusting for
treatment assignment (HRT versus placebo).
†Also adjusted for a history of MI and recent hospitalization.
and Treatment Assignment
Absolute Risk of VTE by Factor V Leiden Genotype
(1000/yr)*95% CI Excess Risk
? ? ?
*Estimated events per 1000 women per year. For both HRT and placebo,
event rates are estimated by treatment assignment from observed genotype
prevalence in cases and controls and VTE event rates in the combined
HERS/ERA cohorts. By virtue of randomization, genotype is assumed to be
unrelated to treatment assignment in the entire study population.
Herrington et alEstrogen and VTE Risk in Women With CHD
to imagine many clinical settings in which the benefits of
postmenopausal HRT would outweigh this increase in risk in
women with existing coronary heart disease (CHD). This is
especially true in light of the evidence that HRT is ineffective
at slowing clinical22,40or anatomic21,41manifestations of
atherosclerosis and may even be associated with an early
increase in CHD events.22,42–44Unfortunately, despite the
higher absolute risk of VTE in women with CHD, the
prevailing costs of $150 to $600 for a single clinical factor V
Leiden determination makes screening impractical. Even if
the low end of this range of cost is assumed, ?$50 000 would
be spent on screening to prevent 1 VTE hospitalization. If
clinical genotyping for factor V Leiden becomes less expen-
sive, screening could become a cost-effective strategy in
women with heart disease.45
In summary, in women with coronary disease, factor V
Leiden and HRT use are independently associated with an
increase in VTE risk. In women who have both risk factors,
the absolute risk is ?1.5% per year. If less expensive methods
for factor V genotyping become more widely available,
screening for factor V Leiden before initiating HRT might
become a cost-effective strategy in women with coronary
disease. However, even in women with coronary disease
without factor V Leiden, the HRT-associated VTE risk must
be carefully considered when HRT is used for approved
This study was supported by grants U01 HL-45488 (Principal
Investigator, D.M. Herrington) and M01 RR-07122 (General Clini-
cal Research Center, Wake Forest University Baptist Medical Cen-
ter) from the National Institutes of Health, Bethesda, Md, and a
contract from Wyeth-Ayerst Research, Radnor, Pa. The authors
thank Georgia Saylor for database construction and analyses, Karen
Craver and Bridget Fitzgerald for the factor V Leiden genotyping,
J.T. Tolentino for research assistance, and Karen Potvin Klein, MA,
ELS, for her invaluable editorial assistance.
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